TY - JOUR
T1 - Pharmacology and Toxicology of Chronically Infused Epidural Clonidine · HCl in Dogs
AU - Yaksh, Tony L.
AU - Rathbun, Michael
AU - Jage, Juergen
AU - Mirzai, Todd
AU - Grafe, Marjorie
AU - Hiles, Richard A.
PY - 1994/10
Y1 - 1994/10
N2 - Pharmacology and Toxicology of Chronically Infused Epidural Clonidine · HCl in Dogs. Yaksh, T. L., Rathbun, M., Jage, J., Mirzai, T., Grafe, M., and Hiles, R. A. (1994). Fundam. Appl. Toxicol. 23, 319-335. To evaluate the physiological effects and toxicity of epidural clonidine · HCl, male Beagle dogs were prepared with chronic lumbar epidural catheters and administered constant infusions of either saline (N = 10), or 80 μg/hr (N = 6), 200 μg/hr (N = 6), or 320 μg/hr (N = 12) clonidine · HCl at a rate of 4 ml/24 hr for 28 days. Saline infusion had no effect upon any behavioral measure. Epidural clonidine produced a dose-dependent increase in thermal skin-twitch response latency (antinociception), lowering of respiration rate, heart rate, and blood pressure, and increased sedation. The effects were maximum from approximately Day 1 to Day 3 when, with the exception of respiration which remained depressed, a progressive adaptation was observed over the course of the study. There were no negative effects on body weight, body temperature, motor function, bowel or bladder function, or clinical pathology values. After 28 days of continuous infusion, the dogs were deeply anesthetized and terminated. Cisternal cerebrospinal fluid taken at termination displayed no clinically significant differences in protein or glucose concentration. All groups, including control, had dogs which had a chronic inflammatory response in the epidural space, as represented by fibrosis, foreign body giant cells, and lymphocytes, but no spinal cord pathology. Both the steadystate plasma and CSF concentrations of clonidine were proportional to the dose; the ratio of CSF to plasma concentration was approximately 0.5. The failure to see any change in CSF composition, significant spinal cord pathology, or signs of tissue or organ toxicity emphasizes the safety of epidurally administered clonidine at infusion rates up to 320/μg/hr and at infusate concentrations up to 2 mg/ml.
AB - Pharmacology and Toxicology of Chronically Infused Epidural Clonidine · HCl in Dogs. Yaksh, T. L., Rathbun, M., Jage, J., Mirzai, T., Grafe, M., and Hiles, R. A. (1994). Fundam. Appl. Toxicol. 23, 319-335. To evaluate the physiological effects and toxicity of epidural clonidine · HCl, male Beagle dogs were prepared with chronic lumbar epidural catheters and administered constant infusions of either saline (N = 10), or 80 μg/hr (N = 6), 200 μg/hr (N = 6), or 320 μg/hr (N = 12) clonidine · HCl at a rate of 4 ml/24 hr for 28 days. Saline infusion had no effect upon any behavioral measure. Epidural clonidine produced a dose-dependent increase in thermal skin-twitch response latency (antinociception), lowering of respiration rate, heart rate, and blood pressure, and increased sedation. The effects were maximum from approximately Day 1 to Day 3 when, with the exception of respiration which remained depressed, a progressive adaptation was observed over the course of the study. There were no negative effects on body weight, body temperature, motor function, bowel or bladder function, or clinical pathology values. After 28 days of continuous infusion, the dogs were deeply anesthetized and terminated. Cisternal cerebrospinal fluid taken at termination displayed no clinically significant differences in protein or glucose concentration. All groups, including control, had dogs which had a chronic inflammatory response in the epidural space, as represented by fibrosis, foreign body giant cells, and lymphocytes, but no spinal cord pathology. Both the steadystate plasma and CSF concentrations of clonidine were proportional to the dose; the ratio of CSF to plasma concentration was approximately 0.5. The failure to see any change in CSF composition, significant spinal cord pathology, or signs of tissue or organ toxicity emphasizes the safety of epidurally administered clonidine at infusion rates up to 320/μg/hr and at infusate concentrations up to 2 mg/ml.
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U2 - 10.1006/faat.1994.1112
DO - 10.1006/faat.1994.1112
M3 - Article
C2 - 7835532
SN - 1096-6080
VL - 23
SP - 319
EP - 335
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 3
ER -